Elevated angiotensin II induces platelet apoptosis through promoting oxidative stress in an AT1R-dependent manner during sepsis.
Elevated angiotensin II induces platelet apoptosis through promoting oxidative stress in an AT1R-dependent manner during sepsis.
复制标题
败血症期间血管紧张素 II 升高通过 AT1R 依赖性方式促进氧化应激诱导血小板凋亡
DOI：
10.1111/jcmm.16382
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发表时间：
2021-04
影响因子：
5.3
通讯作者：
Jiang L
中科院分区：
文献类型：
--
作者：
Xu DF;Liu YJ;Mao YF;Wang Y;Xu CF;Zhu XY;Jiang L
血小板减少与严重脓毒症患者死亡率增加独立相关。脓毒症受试者中的肾素-血管紧张素系统（RAS）升高;累积的研究表明，血管紧张素II（Ang II）通过促进活性氧（ROS）的产生来刺激内源性凋亡途径。然而，血小板凋亡与RAS系统在脓毒症中的作用机制尚未完全阐明。本研究旨在阐明RAS是否参与脓毒症相关性血小板减少症的发病机制，并探讨其潜在机制。我们发现，血浆血管紧张素II升高与血小板计数下降，在脓毒症患者和实验动物暴露于脂多糖（LPS）。此外，在原代分离的血小板中，Ang II处理以浓度依赖性方式诱导血小板凋亡，这可被血管紧张素II 1型受体（AT 1 R）拮抗剂氯沙坦阻断，但不被血管紧张素II 2型受体（AT 2 R）拮抗剂PD 123319阻断。此外，氯沙坦抑制AT 1 R可减弱LPS诱导的血小板凋亡，减轻脓毒症相关的血小板减少症。此外，Ang II处理以浓度依赖性方式诱导原代分离血小板中的氧化应激水平，这被AT 1 R拮抗剂氯沙坦部分逆转。本研究表明，在脓毒症相关血小板减少症中，升高的Ang II通过以AT 1 R依赖性方式促进氧化应激直接刺激血小板凋亡。本研究结果有助于了解RAS系统在脓毒症相关血小板减少症中的作用。
Thrombocytopenia is independently related with increased mortality in severe septic patients. Renin‐angiotensin system (RAS) is elevated in septic subjects; accumulating studies show that angiotensin II (Ang II) stimulate the intrinsic apoptosis pathway by promoting reactive oxygen species (ROS) production. However, the mechanisms underlying the relationship of platelet apoptosis and RAS system in sepsis have not been fully elucidated. The present study aimed to elucidate whether the RAS was involved in the pathogenesis of sepsis‐associated thrombocytopenia and explore the underlying mechanisms. We found that elevated plasma Ang II was associated with decreased platelet count in both patients with sepsis and experimental animals exposed to lipopolysaccharide (LPS). Besides, Ang II treatment induced platelet apoptosis in a concentration‐dependent manner in primary isolated platelets, which was blocked by angiotensin II type 1 receptor (AT1R) antagonist losartan, but not by angiotensin II type 2 receptor (AT2R) antagonist PD123319. Moreover, inhibiting AT1R by losartan attenuated LPS‐induced platelet apoptosis and alleviated sepsis‐associated thrombocytopenia. Furthermore, Ang II treatment induced oxidative stress level in a concentration‐dependent manner in primary isolated platelets, which was partially reversed by the AT1R antagonist losartan. The present study demonstrated that elevated Ang II directly stimulated platelet apoptosis through promoting oxidative stress in an AT1R‐dependent manner in sepsis‐associated thrombocytopenia. The results would helpful for understanding the role of RAS system in sepsis‐associated thrombocytopenia.